The long-term goal of this proposal is to understand specific molecular mechanisms of Tgf-beta signaling that take place during palatal fusion. This is very important since failure of these processes has been shown to lead to cleft palate, one of the most common birth defects in humans. Others and we have previously shown that during palatal fusion transforming growth factor-betas (Tgf-betas) induce several downstream responses that contribute to the successful palatogenesis. This proposal focuses on the role of epithelial and mesenchymal Tgf-beta signals in coordination of palatal fusion. Our overall hypothesis is: Tgf-beta/Bmp signaling events both in the palatal mesenchyme and in the epithelium are critical for successful palatal fusion and play a concerted role during palatogenesis. We propose to test this hypothesis by five Specific Aims. In Aim 1 we propose to determine the effect of neural crest cell specific abrogation of the Tgf-b type I receptor AIk2 on palatal development. In Aim 2, we propose to define the role of Tgf-beta type I receptors AIk2 and AIk5 in the palatal midline epithelium during palatal fusion, in Aim 3 we propose to determine the role of reciprocal epithelio-mesenchymal Tgf-beta signaling during palatal fusion, in Aim 4 we propose to analyze why direct contact between the palatal epithelium and mesenchyme can bypass the Tgf-beta3 signaling defect, and finally in Aim 5 we propose to determine the role of gap junctions in Tgf-beta-induced palatal midline epithelial fusion. Our unique experimental models and the state-of-art strategy allow us to determine the role Tgf-beta signaling via AIk5 and AIk2 in palatogenesis. Collectively, the proposed experiments are likely to be of critical importance in attempting to understand the molecular bases of facial and palatal cleftings in humans, and to develop possible therapeutic approaches to treat cleft palate during the fetal period.